Use of efaroxan and derivatives thereof for the treatment of Alzheimer&#39;s disease

ABSTRACT

The present invention relates to the use of efaroxan and derivatives for the treatment of Alzheimer&#39;s disease.

This application is filed under 35 U.S.C. 371 of PCT/FR94/00841, filed07 Jul. 1994, which claims priority of application 93/08497 filed inFrance 09 Jul. 1993.

The present invention relates to the use of efaroxan and derivatives forthe treatment of Alzheimer-like senile dementia, pre-Alzheimer'ssyndrome, progressive supranuclear palsy and other neurodegenerativediseases.

Alzheimer's disease is a progressive neurodegenerative diseaseparticularly, but not exclusively, affecting the central cholinergicsystem (Meynert's nucleus basalis) manifested by a loss of cognitivefaculties, a loss of intellectual capacities, and behavioral andpersonality disorders.

There is currently no satisfactory treatment either for treating thesymptoms or for slowing its advancement. Diagnosis of the disease isdifficult, and one can never be certain about diagnosing Alzheimer'sdisease per se. It is in particular the anatomohistological analysisperformed post-mortem by, inter alia, the revelation of extraneuronalsenile plaques and intraneuronal neurofibrillar networks which makes itpossible to diagnose Alzheimer's disease unambiguously. A loss ofcellular bodies and a depletion of neurotransmitters, in particularacetylcholine, are also associated therewith. In the absence of thishistological and biochemical proof, the clinical characteristics lead tothe diagnosis of a pre-Alzheimer-like neurodegenerative disease.

"Progressive Supranuclear Palsy" (PSP) is a non-hereditary evolutiveneurodegenerative disease which appears late and involves perturbationsof several neurotransmitters. PSP is characterized by dementia withpostural instability, rigidity, associated bradykinesia, accompanied bysupranuclear ophthalmoplegia. This disease appears in about 4% ofpatients suffering from Parkinsonism. There is currently no treatmentfor this disease. Palliative or symptomatological therapies do not havea satisfactory effect.

It is known that efaroxan,2-(2-ethyl-2,3-dihydrobenzofuranyl)-2-imidazoline, possesses antagonistproperties with respect to α₂ -adrenergic receptors. This compound isdescribed in patent application GB-2,102,422 along with its therapeuticapplication as an anti-depressant and antimigraine medicinal product.

This compound and derivatives thereof are also described in patentapplication WO 92/05171 in which the action of the levorotatoryenantiomer for treating diabetes and the action as a potassium channelblocking agent are demonstrated.

The present invention relates to the use of efaroxan and derivativesthereof for the preparation of a medicinal product intended for thetreatment of Alzheimer-like senile dementia, pre-Alzheimer's syndrome,progressive supranuclear palsy and other neurodegenerative diseases.

The expression efaroxan and derivatives thereof is understood to meanthe compound of formula I ##STR1## in which R₁ represents a hydrogenatom or a linear or branched C₁ -C₆ alkyl radical,

R₂ represents a hydrogen atom or a methyl, chloro, bromo or fluorogroup, and

R₃ represents a hydrogen atom or a methyl, hydroxyl, methoxy, fluoro,chloro or bromo group, and

the therapeutically acceptable salts thereof, the racemic mixturethereof or the optically active isomers thereof.

Advantageously, R₂ and R₃ represent a hydrogen atom and R₁ represents anethyl, n-propyl or i-propyl group.

The compound of general formula I is preferably chosen from thefollowing compounds:

2-(2-ethyl-2,3-dihydrobenzofuranyl)-2-imidazoline,

2-(2-n-propyl-2,3-dihydrobenzofuranyl)-2-imidazoline,

2-(2-i-propyl-2,3-dihydrobenzofuranyl)-2-imidazoline.

PHARMACOLOGICAL STUDY

A study on the activity of efaroxan on rat memory functions wasperformed in accordance with the described conditions (P. CHOPIN and M.BRILEY, Psychopharmacology 106, 26 (1992)).

When administered before the first passive avoidance behavior trainingsession, scopolamine, a central antagonist, induces a dose-dependentamnesia which may be measured 48 hours later during a second session.

The administration of efaroxan, 30 minutes before the second session,decreases the amnesia induced by scopolamine, thus showing an increasein nmemonic activity by stimulation of the memory functions.

The table below shows the effect of efaroxan in the presence ofscopolamine, in a dose-dependent manner, in increasing the time requiredfor the rat to pass from a lit compartment to a dark compartment whereit receives a small electric shock. The percentage of the effect isgiven in the 3rd column.

    ______________________________________                                               Dose mg/kg                                                                    entrance   delay time                                                                              % significant                                            i.p.       (sec)     effect                                            ______________________________________                                        Efaroxan 0            28.6 ± 11.6                                                   0.04         38.3 ± 16.2                                                                          +34                                                    0.16         56.0 ± 15.3                                                                          +96                                           ______________________________________                                    

The above results show the advantage of using efaroxan as a medicinalproduct in order to improve the memory functions and in order to improvethe symptomatology of Alzheimer's disease.

PHARMACEUTICAL STUDY

The pharmaceutical compositions are administered orally in the form ofgelatin capsules or tablets containing a dose of 1 to 100 mg of activeprinciple, more particularly of 2, 5 and 20 mg per capsule, orintravenously in the form of an injectable solution containing a dose of0.1 to 10 mg of efaroxan.

CLINICAL STUDY

Efaroxan was administered at a dose of 2 to 20 mg per dosage intake perday for 6 months, to patients who had manifested memory disorders,symptoms of cognitive deficiencies and behavioral disorders suggesting apre-Alzheimer syndrome. The results on the overall symptomatology showeda benefit in 30% of the cases.

PSP CLINICAL STUDY

12 patients suffering from PSP received efaroxan, at a dose of 2 mg 3 or4 times per day for 4 weeks, in comparison with an identical periodduring which a placebo was administered.

After the study, the comparison is in favor of the period treated withefaroxan, during which the symptomatology observed is improved, as arethe usual grade scores and likewise the cognitive and mood tests formore than 30% of the cases.

We claim:
 1. Method for the treatment of Alzheimer-like senile dementia,pre-Alzheimer's syndrome, and progressive supranuclear palsy, in amammal suffering therefrom, comprising the step of administering to thesaid mammal an amount of a compound selected from those of formula I##STR2## in which R₁ represents hydrogen or linear or branched C₁ -C₆alkyl,R₂ represents hydrogen or methyl, chloro, bromo, or fluoro, and R₃represents hydrogen or methyl, hydroxyl, methoxy, fluoro, chloro, orbromo, and a therapeutically-acceptable salt thereof, a racemic mixturethereof, and an optically-active isomer thereof, which is effective forsaid purpose.
 2. Method of claim 1, wherein R₂ and R₃ represent ahydrogen atom.
 3. Method of claim 1, wherein R₁ represents an ethyl,n-propyl, or i-propyl group.
 4. Method of claim 2, wherein R₁ representsan ethyl, n-propyl, or i-propyl group.
 5. Method of claim 1, wherein thecompound is selected from the group consistingof:2-(2-ethyl-2,3-dihydrobenzofuranyl)-2-imidazoline,2-(2-n-propyl-2,3-dihydrobenzofuranyl)-2-imidazoline, and2-(2-i-propyl-2,3-dihydrobenzofuranyl)-2-imidazoline.